Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• asymmetrically substituted derivatives at phenanthridine side-rings and unsubstituted central ring [24]. The recently reported photo-conversion of various isocyanide biphenyls into alkylated phenanthridine derivatives under rather mild reaction conditions introduced several novelties (Scheme 8) [25]. The most

• also implemented in the two-component cyclization in the synthesis of phenanthridine derivatives [38]. The starting isocyanide biphenyl (similar to Scheme 8) reacts with the phenyl radical generated from phenylboronic acid and a manganese salt followed by spontaneous cyclisation and aromatisation

Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach

• András Demjén,
• Márió Gyuris,
• János Wölfling,
• László G. Puskás and
• Iván Kanizsai

Beilstein J. Org. Chem. 2014, 10, 2338–2344, doi:10.3762/bjoc.10.243

• synthetic elaboration of a green-compatible isocyanide-based access in three-component mode, we describe an operationally simple, one-pot two-step GBB protocol for the rapid construction of a 46 membered imidazo[1,2-b]pyrazole library with yields up to 83%. Keywords: Groebke–Blackburn–Bienaymé reaction; 1H

• -imidazo[1,2-b]pyrazole; isocyanide; multicomponent reaction; N-heterocycles; Introduction For the relatively rapid design and construction of a diverse, large pharmacophore library, the basic concepts of diversity-oriented synthesis and isocyanide-based multicomponent reactions, such as the Ugi four

• -aminopyrazole-4-carbonitrile (1a), p-tolualdehyde (2a) and tert-butyl isocyanide (3a) in order to elucidate the structure of the product and investigate the regioselectivity. The synthesis of 5-aminopyrazole-4-carbonitrile (1a) was based on a literature method [43][44]. A single product was observed in a yield

Photochemical approach to functionalized benzobicyclo[3.2.1]octene structures via fused oxazoline derivatives from 4- and 5-(o-vinylstyryl)oxazoles

• Ivana Šagud,
• Simona Božić,
• Željko Marinić and
• Marija Šindler-Kulyk

Beilstein J. Org. Chem. 2014, 10, 2222–2229, doi:10.3762/bjoc.10.230

• isocyanide (TosMIC) [38][39]. For the preparation of 5-(2-vinylstyryl)oxazole (2) by this method 3-(2-vinylphenyl)acrylaldehyde (6) was needed. This new o-substituted phenylacrylaldehyde 6 was prepared using (formylmethylene)triphenylphosphorane by a Wittig reaction from o-vinylbenzaldehyde (5). The yield of

Synthesis of α-amino amidines through molecular iodine-catalyzed three-component coupling of isocyanides, aldehydes and amines

• Praveen Reddy Adiyala,
• D. Chandrasekhar,
• Jeevak Sopanrao Kapure,
• Chada Narsimha Reddy and
• Ram Awatar Maurya

Beilstein J. Org. Chem. 2014, 10, 2065–2070, doi:10.3762/bjoc.10.214

• economy, wide substrate scope and high yields. Keywords: α-amino amidines; iodine; isocyanide; multicomponent reaction; Ugi reaction; Introduction Amidines are a class of organic compounds exhibiting a variety of biological activity that makes them potential candidates for drug development and discovery

• were found suitable for conversion of substrates into products when water was used as a nucleophile for amide preparations [13][14]. In the direction of amidine synthesis using isocyanide MCRs, a few catalysts such as p-toluenesulfinic acid [15], metal triflates [16], bromodimethylsulfonium bromide [17

• reaction, we carried out a model reaction of tert-butyl isocyanide (1 mmol), benzaldehyde (1 mmol), and aniline (2 mmol) using 5 mol % of molecular iodine in methanol (Table 1). The reaction worked well at ambient temperature and led to good yields of 4a. Among various solvents screened, methanol was found

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• aldehyde), an amine, an isocyanide, and a carboxylic acid (Scheme 13) [77][78]. The Ugi MCRs involving a nucleoside as the substrate bearing the formyl, amino, or isocyano group have been reported. The four-component Ugi reaction employing 3',5'-di-O-acetyl-5-formyl-2'-deoxyuridine (14) as the key

• step was successfully accomplished by Tsuchida et al. (Scheme 15) [80]. The isopropylidene-protected 3-(2-formylethyl)uridine 32, 2-(aminomethyl)pyridine 1-oxide, cyclohexenyl isocyanide, and acetic acid were allowed to react under ambient conditions for 24 h to yield the expected product 33. Further

• synthesis was executed in 96-well plates, with one of the two amines 47, 12 carboxylic acids, 8 aldehydes, and an isocyanide per plate. The products 49 were cleaved from the support with HF/pyridine in THF. As expected, the Ugi products 49 were obtained as ca. 1:1 mixtures of diasteroisomers (based on HPLC

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• methodologies to access chiral 3,3-disubstituted 3-aminooxindoles [16][17][18][19], we looked at isocyanide-based multicomponent reactions as a possible efficient tool to quickly prepare oxindole-based peptidomimetic compounds [20][21][22]. Despite the synthetic efficiency of the Ugi reaction and its wide

• application in combinatorial and medicinal chemistry [23][24][25][26][27][28], to the best of our knowledge a synthesis of 3,3-disubstituted 3-aminooxindoles which relies on isocyanide-based multicomponent reactions has not been unexplored yet. Although in this kind of reaction a new stereogenic center is

• examples with satisfactory selectivity were achieved to date [32][33][34][35][36]. Results and Discussion Relying on our previous experience, we selected chiral ketimine 1 as a suitable substrate and started to investigate the Ugi three-component reaction (3CR) with tert-butyl isocyanide (2a) and

Consecutive isocyanide-based multicomponent reactions: synthesis of cyclic pentadepsipeptoids

• Angélica de Fátima S. Barreto,
• Otilie E. Vercillo,
• Ludger A. Wessjohann and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2014, 10, 1017–1022, doi:10.3762/bjoc.10.101

• sansalvamide A is described. An efficient and fast synthetic strategy was developed using a combination of consecutive isocyanide-based multicomponent reactions (Ugi and Passerini reactions). This methodology can be used to access a variety of cyclic oligodepsipeptoids. Keywords: depsipeptoids; multicomponent

• added under pseudo-high dilution conditions (addition rate: 0.6 mL/h; addition time: 83 h; concentration: 0.80 mmol/L) to a suspension of paraformaldehyde 4, triethylamine, sodium sulfate and isopropyl/isobutyl/tert-butyl isocyanide 12a–c in methanol to yield the target cyclic pentadepsipeptoids 2a–f

• can be obtained by changes in the amine component in the first Ugi reaction, in the carbonyl component in the Passerini reaction or in the isocyanide and carbonyl components in the macrocyclization step. The general route and procedure developed allows an easy access to complex molecules with a

The Ugi four-component reaction as a concise modular synthetic tool for photo-induced electron transfer donor-anthraquinone dyads

• Sarah Bay,
• Gamall Makhloufi,
• Christoph Janiak and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2014, 10, 1006–1016, doi:10.3762/bjoc.10.100

• anthraquinone-substituted aldehyde together with acetic acid and tert-butyl isocyanide for rapidly assembling a donor–acceptor conjugate 1 displaying a photo-induced electron transfer leading to a charge-separated state with a lifetime of >2 ns (Figure 1), as elucidated by femtosecond transient absorption

• -butyl isocyanide (7) were the two residual components (Scheme 1) [56]. The most favorable solvent for Ugi 4CR is methanol. However, to increase solubility portions of dichloromethane were added to assure a homogeneous solution. For liberating the free base from methylamine hydrochlorides 4, potassium

• -only systems 10 were also prepared by Ugi 4CR from the amino derivatives 4 and acetaldehyde (9), in moderate to good yield, with acetic acid (6) and tert-butyl isocyanide (7) as the corresponding acid and isonitrile components (Scheme 2). The appearance of single signal sets in the 1H and 13C NMR

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• structural diversity and molecular complexity in only one step. Among the MCRs, the isocyanide-based multicomponent reactions (IMCRs) are most relevant for the synthesis of peptidomimetics because they provide peptide-like products. However, these IMCRs usually give linear products and in order to obtain

• ideally suited for automated synthesis [14][15][16][17][18]. Among the MCRs, the isocyanide-based multicomponent reactions (IMCRs), such as the Ugi and the Passerini reaction, are the most relevant reactions for constructing peptidomimetics since they give access to (depsi)peptide-like structures. However

• rings (9–12 membered) to macrocycles. Isocyanide-based multicomponent reactions for cyclic peptidomimetics Multicomponent reactions that include isocyanide or isocyanide derivatives (e.g. isocyanoacetates) have been widely applied for the synthesis of peptidomimetics. The main advantage of these

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• synthesis of the imidazole core structure via a Mannich-type condensation of imines. An alternative method to activate the α-carbon atom of an isocyanide group as a nucleophile is the coordination of a metal at the terminal carbon in the isocyanide group resulting in an increase in the acidity of the α

• substituents by using methanol as a solvent. Further improvements can be achieved in the presence of a catalytic amount of AgOAc acting as a Lewis acid to improve the α-acidity of the isocyanide component. However, the presence of an electron withdrawing group in α-position of 61 is essential in any case

• (Scheme 33) [90][91]. The reaction occurs via a Mannich-type addition of the deprotonated isocyanide intermediate 64 to an in situ generated iminium salt, a subsequent intramolecular cyclization and proton shift results in dihydroimidazole 65 showing predominantly cis-arrangment around the C4–C5 bond

An oxidative amidation and heterocyclization approach for the synthesis of β-carbolines and dihydroeudistomin Y

• Suresh Babu Meruva,
• Akula Raghunadh,
• Raghavendra Rao Kamaraju,
• U. K. Syam Kumar and
• P. K. Dubey

Beilstein J. Org. Chem. 2014, 10, 471–480, doi:10.3762/bjoc.10.45

• (1) are generally carried out either from indole or its suitably substituted derivatives. The acylation of 2-(3-indolyl)ethyl isocyanide with phenylacetyl chloride followed by cyclization and aromatization is well documented in the literature for the synthesis of 1-benzoyldihydro-β-carbolines. The

Diversity-oriented synthesis of dihydrobenzoxazepinones by coupling the Ugi multicomponent reaction with a Mitsunobu cyclization

• Lisa Moni,
• Luca Banfi,
• Andrea Basso,
• Alice Brambilla and
• Renata Riva

Beilstein J. Org. Chem. 2014, 10, 209–212, doi:10.3762/bjoc.10.16

• reaction of an ortho-(benzyloxy)benzylamine, glycolic acid, an isocyanide and an aldehyde, followed by an intramolecular Mitsunobu substitution was developed. The required ortho-(benzyloxy)benzylamines have been in situ generated from the corresponding azides, in turn prepared in high yields from salicylic

• continuous interest in the use of isocyanide based MCRs in the synthesis of seven-membered heterocycles [4][5][6][7] has now prompted us to extend the methodology to the synthesis of 2,3-dihydrobenzo[f][1,4]oxazepin-3-ones 10, which represent a typical drug-like scaffold, already demonstrated to be useful in

• water (4 mmol, 68 μL) was added and the mixture was further stirred for 1 h. The solvent was evaporated and the crude taken up in dry methanol (2.5 mL) and treated with 3 Å powdered molecular sieves (50 mg). Glycolic acid (1.2 mmol) and the appropriate aldehyde and isocyanide (1.2 mmol each) were added

Synthesis and biological activity of N-substituted-tetrahydro-γ-carbolines containing peptide residues

• Nadezhda V. Sokolova,
• Valentine G. Nenajdenko,
• Vladimir B. Sokolov,
• Daria V. Vinogradova,
• Elena F. Shevtsova,
• Ludmila G. Dubova and
• Sergey O. Bachurin

Beilstein J. Org. Chem. 2014, 10, 155–162, doi:10.3762/bjoc.10.13

• (1 mmol) and isocyanide 4 (1 mmol) were added at room temperature. The mixture was stirred for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography (hexanes/ethyl acetate) to give compounds 5. General procedure for the synthesis of compounds 6a–g: To a solution

Studies on the interaction of isocyanides with imines: reaction scope and mechanistic variations

• Ouldouz Ghashghaei,
• Consiglia Annamaria Manna,
• Esther Vicente-García,
• Marc Revés and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2014, 10, 12–17, doi:10.3762/bjoc.10.3

• Barcelona, Spain 10.3762/bjoc.10.3 Abstract The interaction of imines with isocyanides has been studied. The main product results from a sequential process involving the attack of two units of isocyanide, under Lewis acid catalysis, upon the carbon–nitrogen double bond of the imine to form the 4-membered

• ring system. The scope of the reaction regarding the imine and isocyanide ranges has been determined, and also some mechanistic variations and structural features have been described. Keywords: azetidines; heterocycles; imines; isocyanides; multicomponent reactions; Introduction The interaction of

• direct reaction of imines and isocyanides has been considerably less studied and, in the absence of a carboxylate, the mechanistic outcome is considerably modified [2]. A relevant precedent was described by Deyrup in the late sixties, demonstrating the double incorporation of an isocyanide moiety to an

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

Methylidynetrisphosphonates: Promising C₁ building block for the design of phosphate mimetics

• Vadim D. Romanenko and
• Valery P. Kukhar

Beilstein J. Org. Chem. 2013, 9, 991–1001, doi:10.3762/bjoc.9.114

• ). Trisphosphonate 2 is also formed by the reaction of [(EtO)2P(O)]2C(Cl)NCO as well as (EtO)2P(O)CCl2NCO with 1 or 2 equiv of (EtO)3P, correspondingly [21]. An unsuccessful attempt to synthesize trisphosphonates from isocyanide dichlorides was made by the combination of Arbuzov reaction and dialkyl phosphite

4-Pyridylnitrene and 2-pyrazinylcarbene

• Curt Wentrup,
• Ales Reisinger and
• David Kvaskoff

Beilstein J. Org. Chem. 2013, 9, 754–760, doi:10.3762/bjoc.9.85

• and 2120 cm−1 (Figure 4 and Supporting Information File 1, Figure S4 and Figure S5). The group of bands at 2028–2060 cm−1 is ascribed to the ketenimine moiety (N=C=C), and the band at 2120 cm−1 to the isocyanide (NC) function in the ring-opened N-(isocyanovinyl)ketenimine (27) (Scheme 4). The latter

• matrix. Also the isocyanide band at 2120 cm−1 shows splitting, but this is less well resolved (Figure 4). All this makes it difficult to assign other, much weaker, peaks in the IR spectra to compound 27. However, the following bands, which are not ascribed to the cyclic ketenimine 20, can be assigned to

A one-pot catalyst-free synthesis of functionalized pyrrolo[1,2-a]quinoxaline derivatives from benzene-1,2-diamine, acetylenedicarboxylates and ethyl bromopyruvate

• Mohammad Piltan,
• Loghman Moradi,
• Golaleh Abasi and
• Seyed Amir Zarei

Beilstein J. Org. Chem. 2013, 9, 510–515, doi:10.3762/bjoc.9.55

• )anilines with alkynes to form 4,5-dihydropyrrolo[1,2-a]quinoxalines [23][24]. Kobayashi and co-workers have described the Lewis acid catalyzed cyclization of 1-(2-isocyanophenyl)pyrroles to give pyrrolo[1,2-a]quinoxalines in good yields; however, the isocyanide substrates required multistep synthesis [25

Synthetic studies towards bottromycin

• Stefanie Ackermann,
• Hans-Georg Lerchen,
• Dieter Häbich,
• Angelika Ullrich and
• Uli Kazmaier

Beilstein J. Org. Chem. 2012, 8, 1652–1656, doi:10.3762/bjoc.8.189

• in the amidination step. For this approach we first needed the isocyanide 7 derived from (S)-tert-leucine methyl ester. According to Ugi et al. this isocyanide was obtained in enantiomerically pure form from the corresponding formamide 6 by dehydration with POCl3/NEt3 (Scheme 3). This isocyanide was

Metal–ligand multiple bonds as frustrated Lewis pairs for C–H functionalization

• Matthew T. Whited

Beilstein J. Org. Chem. 2012, 8, 1554–1563, doi:10.3762/bjoc.8.177

• iridium center was utilized to explore a variety of atom- and group-transfer reactions, as described above. However, the iridium carbonyl, thiocarbonyl, or isocyanide products thus generated could not be incorporated into catalytic cycles due to the stability of the Ir–CO, –CS, and –CNR bonds [71][91]. A

Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

• Ricardo A. W. Neves Filho,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2011, 7, 1504–1507, doi:10.3762/bjoc.7.175

• , and melting point of 1 were consistent with the reported data [2][14][15]. For the diversity oriented synthesis the advanced intermediate 5 was used as the amino component in an Ugi-4CR with (S)-2-methylbutanoic acid, hydrophobic amino acids, formaldehyde and tert-butyl isocyanide (Scheme 2). These

• addition of (S)-2-methylbutanoic acid, Boc-Gly, Boc-Ala, Boc-Val, Boc-Leu, Boc-Phe and Boc-Ile and tert-butyl isocyanide. Following this procedure, the desired optically active compounds 6a–g were obtained in 55–63% yields. Their structures were confirmed by 1H, 13C NMR and HRMS spectra. Finally, the Ugi

Ugi post-condensation copper-triggered oxidative cascade towards pyrazoles

• Aurélie Dos Santos,
• Laurent El Kaim,
• Laurence Grimaud and
• Caroline Ronsseray

Beilstein J. Org. Chem. 2011, 7, 1310–1314, doi:10.3762/bjoc.7.153

• ; isocyanide; pyrazolidinone; Introduction In the last twenty years, the Ugi reaction coupled with its various post-condensations towards heterocyclic libraries has established the success of isocyanide-based multicomponent reactions [1][2][3][4][5][6][7]. Chemists in both academia and industry have taken

• MeOH under standard Ugi conditions, led to the formation of the amide 2a in 64% isolated yield. The compatibility of the hydrazone with this coupling is certainly due to the higher electrophilicity of the intermediate iminium. The latter traps the isocyanide before any interaction with the hydrazone

Multicomponent synthesis of artificial nucleases and their RNase and DNase activity

• Anton V. Gulevich,
• Lyudmila S. Koroleva,
• Olga V. Morozova,
• Valentina N. Bakhvalova,
• Vladimir N. Silnikov and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2011, 7, 1135–1140, doi:10.3762/bjoc.7.131

• activity of the new compounds towards single-stranded RNA and double-stranded circular DNA. Keywords: DNA; isocyanide; multicomponent reaction; organocatalysis; peptidomimetic; RNA; Introduction RNA cleavage can serve as a molecular tool for biological research [1], as well as for development of

• especially important because multicomponent reactions (MCR) could be adapted to a high throughput synthesis of libraries of compounds. It is known that isocyanide-based MCR are very efficient for synthesis of peptides and peptide molecules [19][20][21][22][23][24]. We proposed that the desired compounds 5

• ); 13C NMR (100 MHz, CDCl3) δ 155.6 (t, J = 5.9 Hz, NC), 41.1 (t, J = 6.6 Hz, (CH2CH2CH2NC)2), 28.5, 25.2; IR (cm−1) 2150 (NC); Anal. calcd for C8H12N2: C, 70.55; H, 8.88; found: C, 70.34; H, 8.62. General procedure for the synthesis of 4a–g The corresponding isocyanide 3 (3 mmol) and phenyl phosphinic

Novel synthesis of pseudopeptides bearing a difluoromethyl group by Ugi reaction and desulfanylation

• Jingjing Wu,
• Hui Li and
• Song Cao

Beilstein J. Org. Chem. 2011, 7, 1070–1074, doi:10.3762/bjoc.7.123

• out with Merck 60 (230–400 mesh) silica gel. General procedure for compounds 3a–m To a stirred amine (1 mmol), the aldehyde (1 mmol) was added in portions for about 5 min. The mixture was stirred for 30 min at rt. Then, the reaction mixture was heated to 60 °C, and isocyanide (1 mmol) and 2,2-difluoro